Imaging in Oncology Clinical Trials Susan Galbraith Clinical Discovery Bristol-Myers Squibb.

Imaging in Oncology Clinical Trials

Susan Galbraith

Clinical Discovery

Bristol-Myers Squibb

What can we see?

• Microvasculature– Blood volume - MRI, PET– Vessel permeability - MRI– Blood flow - PET, MRI, SPECT– Hypoxia - MRI, PET– VEGF - PET

What can we see?

• Gene expression - optical imaging, PET• Enzyme activation - optical imaging, MRI• Receptor expression/occupancy - PET, MRI• Apoptosis - MRI, PET, SPECT• Cell proliferation - PET• Glucose metabolism - PET• Membrane turnover - PET

Imaging Blood Flow -15O -PET

Yamaguchi et al Cancer 2000

CT PET -Anatomy and Glucose Metabolism

Ken Krohn University of Washington

FLT PET - Imaging Proliferation

• FLT (3’- deoxy-3’ – fluorothymidine) is phosphorylated by thymidine kinase 1 and trapped within cells

• Since TK-1 levels increase around 10-fold in S-phase, retention should theoretically reflect DNA synthesis

Shields et al. Nature Med 1998

Imaging Proliferation

Grant Macarthur - Peter Mac, Australia

DCE-MRI

• Using Gd-DTPA - composite of vessel permeability, surface area and blood flow

• Using high molecular weight contrast agents - permeability, blood volume

• Need arterial input function to determine blood flow

DCE-MRI - Ktrans

MRI - Imaging of permeability and blood volume

• Need high molecular weight contrast agent – Albumin- GdDTPA - Overexpression of VEGF

165 drives peritumor interstitial convection and induces lymphatic drain (Dafni et al Cancer Res 2002)

– Superparamagnetic iron oxide contrast agents

What can imaging do for you?….Novel imaging technology has the potential to • assist lead compound selection• enable earlier Go/No Go decisions• have greater confidence about those decisions• save patients from treatment with drugs destined to fail• save money

How to utilize this potential to truly affect decisions in drug development ?

Objectives of Phase I Oncology Trials

• Safety

• Pharmacokinetics

• Dose selection– cytotoxics - ‘maximum tolerated dose’– ‘targeted’ drugs - ‘optimal biological dose’

What answers would help a novel ‘targeted’ oncology drug?

• Pre-clinical/Phase 1– does the drug hit the target in the tumor– what is the exposure response / time course of response

• Phase I/II– how does hitting target relate to anti-tumor efficacy– any early indicators of toxicity

• Phase II/III– can tumor response be predicted by target expression/ activation– differentiation from competitors

Definition of Go/No Go

• Drug does not hit target

• Do not achieve desired effect size at tolerable doses

• Selectivity of effect in tumor/normal tissues

Where does imaging fit in development?

• SAD (if TI allows) - rapidly define single dose PK, tolerability, ability to reach exposure range for efficacy

• MAD - imaging or other biomarker to demonstrate biological activity, dose response and PK/PD relationship

FDHT-PETPre-flutamide Post-flutamide

MIR Mallinckrodt Instituteof Radiology

FDHT-PET

Transaxial

Pre Flutamide Post Flutamide

Patient with prostate cancer and bony metastasis - Right ilium

MIR Mallinckrodt Instituteof Radiology

Phase I trial

• Dose escalate ? To MTD (depends on TI)

• Expand cohorts for imaging studies (n depends on reproducibility and effect size of interest)

• Need same imaging protocol implemented at all sites

• Quality control

• Centralized data analysis

Implications• Technology used - relatively established vs ‘cutting edge’

• Definition of every stage of imaging process

• Reproducibility studies needed before measurement of treatment effect

• SDV as detailed as for clinical aspects of study

• Site selection

• Consensus on methodology e.g. EORTC FDG PET recommendations 1999

Reproducibility studies

NMR in Biomed 2002, 15, p132-142

Reproducibility Studies• Determine 95% limits of change for individuals

and for groups

• Identify ‘key determinants’ of reproducibility - how much is dependent on subjective definition of ‘ROI’s etc

• Learning curve for technique

• Project cohort size needed for measurement of treatment effect

Choice of parameter• DCE-MRI - gradient, enhancement, AUC,

Ktrans, kep, ve

• FDG PET - dynamic, SUV - which SUV?

• Balance - – reproducibility– sensitivity to treatment effect– validity of assumptions– availability– heterogeneity effect

DCE-MRI response to CA4P

Galbraith et al J Clin Oncol In Press

Choice of patient population

• Homogeneous tumor type, site

• Ability to obtain good quality images - respiration/movement artefact

• Ability to accrue trial within reasonable time

Phase II - Efficacy

• Is stable disease indicative of anti-tumor efficacy?

• Effects on tumor metabolism/ proliferation/ microvasculature seen before effects on tumor size

• Are changes in proliferation/ metabolism seen in higher proportion of patients than proportion with PR/CR

MIR Mallinckrodt Instituteof Radiology

tumor

TransverseCoronal

tumor

Coronal

tumor

Transverse

1 h-post injection 2 h-post injection

tumor

bladder

heart

heart

bladder

18F-FLT PET Images before Treatment

intestineintestine

heart

liver

MIR Mallinckrodt Instituteof Radiology

18F-FLT microPET®; Monitoring Therapy

DES

tumor

tumor

Castration

Before 1 week 2 week 3 week

Control

tumor

By week 3 all control mice were euthanized following Institutional Regulations on tumor burden.

MIR Mallinckrodt Instituteof Radiology

Change in Tumor Volume

Change of Tumor Volume

0

5001000

1500

2000

25003000

3500

4000

0w 1w 2w 3w

Tu

mo

r V

olu

me

(mm

3)

DES

Castration

Control

*

**

* only n=2 survived to week 2** no animals survived

Change of 18F-FLT Uptake in Tumor

MIR Mallinckrodt Instituteof Radiology

Ratios of Tumor vs. Muscle with Backgroud: At 1 hr

0

1

2

3

4

5

0 week 1 week 2 week 3 week

Tu

mo

r/M

uc

le R

ati

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DES

Castration

Control

* only n=2 survived to week 2** no animals survived

*

**

Rationale for use of FDG PET for response assessment

• Earlier response assessment

• Better predictor of clinical benefit than conventional imaging - biology rather than anatomy

• ? Increased number of responders - more information on ‘stable disease’

Will FLT be more informative than FDG for response assessment?

FDG

FLT

Grant Macarthur - Peter Mac, Australia

Phase II/III - response prediction

• Whole tumor imaging characteristics vs tissue biopsy

• Implications of tumor heterogeneity

• Serial non-invasive images vs serial biopsies

Potential utility of imaging..• Imaging of receptor occupancy/ enzyme inhibition

• Pre-clinical correlation with anti-tumor effect

• Understanding of PK/PD relationship

• Translatable technology from pre-clinic to clinic

• Determination of reproducibility in clinic

• High quality, multi-site imaging in trials

• Early indication of efficacy

• Response prediction

How do we get there?• Collaboration with academia - long term

– limits of the technologies possible now– translational studies– what’s around the corner?

• Work on QA/ imaging monitoring/analysis– delivery of high quality imaging in trials

• Develop internal understanding of and expertise in imaging technology